Model For Aging Research Research Articles

Nerve growth factor in the adult brain of a teleostean model for ageing research: Nothobranchius furzeri

Nerve growth factor in the adult brain of a teleostean model for ageing research: Nothobranchius furzeri

The Mitochondrial Genome of Arctica islandica; Phylogeny and Variation

Arctica islandica is known as the longest-lived non-colonial metazoan species on earth and is therefore increasingly being investigated as a new model in aging research. As the mitochondrial genome is associated with the process of aging in many species and bivalves are known to possess a peculiar mechanism of mitochondrial genome inheritance including doubly uniparental inheritance (DUI), we aimed to assess the genomic variability of the A. islandica mitochondrial DNA (mtDNA). We sequenced the complete mitochondrial genomes of A. islandica specimens from three different sites in the Western Palaearctic (Iceland, North Sea, Baltic Sea). We found the A. islandica mtDNA to fall within the normal size range (18 kb) and exhibit similar coding capacity as other animal mtDNAs. The concatenated protein sequences of all currently known Veneroidea mtDNAs were used to robustly place A. islandica in a phylogenetic framework. Analysis of the observed single nucleotide polymorphism (SNP) patterns on further specimen revealed two prevailing haplotypes. Populations in the Baltic and the North Sea are very homogenous, whereas the Icelandic population, from which exceptionally old individuals have been collected, is the most diverse one. Homogeneity in Baltic and North Sea populations point to either stronger environmental constraints or more recent colonization of the habitat. Our analysis lays the foundation for further studies on A. islandica population structures, age research with this organism, and for phylogenetic studies. Accessions for the mitochondrial genome sequences: KC197241 Iceland; KF363951 Baltic Sea; KF363952 North Sea; KF465708 to KF465758 individual amplified regions from different speciemen

Oxidative damage and cellular defense mechanisms in sea urchin models of aging

The free radical, or oxidative stress, theory of aging proposes that the accumulation of oxidative cellular damage is a major contributor to the aging process and a key determinant of species longevity. This study investigates the oxidative stress theory in a novel model for aging research, the sea urchin. Sea urchins present a unique model for the study of aging because of the existence of species with tremendously different natural life spans, including some species with extraordinary longevity and negligible senescence. Cellular oxidative damage, antioxidant capacity, and proteasome enzyme activities were measured in the tissues of three sea urchin species: short-lived Lytechinus variegatus, long-lived Strongylocentrotus franciscanus, and Strongylocentrotus purpuratus, which has an intermediate life span. Levels of protein carbonyls and 4-hydroxynonenal measured in tissues (muscle, nerve, esophagus, gonad, coelomocytes, ampullae) and 8-hydroxy-2′-deoxyguanosine measured in cell-free coelomic fluid showed no general increase with age. The fluorescent age pigment lipofuscin, measured in muscle, nerve, and esophagus, increased with age; however, it appeared to be predominantly extracellular. Antioxidant mechanisms (total antioxidant capacity, superoxide dismutase) and proteasome enzyme activities were maintained with age. In some instances, levels of oxidative damage were lower and antioxidant activity higher in cells or tissues of the long-lived species compared to the short-lived species; however, further studies are required to determine the relationship between oxidative damage and longevity in these animals. Consistent with the predictions of the oxidative stress theory of aging, the results suggest that negligible senescence is accompanied by a lack of accumulation of cellular oxidative damage with age, and maintenance of antioxidant capacity and proteasome enzyme activities may be important mechanisms to mitigate damage.

Characterization of plasma thiol redox potential in a common marmoset model of aging

Due to its short lifespan, ease of use and age-related pathologies that mirror those observed in humans, the common marmoset (Callithrix jacchus) is poised to become a standard nonhuman primate model of aging. Blood and extracellular fluid possess two major thiol-dependent redox nodes involving cysteine (Cys), cystine (CySS), glutathione (GSH) and glutathione disulfide (GSSG). Alteration in these plasma redox nodes significantly affects cellular physiology, and oxidation of the plasma Cys/CySS redox potential (EhCySS) is associated with aging and disease risk in humans. The purpose of this study was to determine age-related changes in plasma redox metabolites and corresponding redox potentials (Eh) to further validate the marmoset as a nonhuman primate model of aging. We measured plasma thiol redox states in marmosets and used existing human data with multivariate adaptive regression splines (MARS) to model the relationships between age and redox metabolites. A classification accuracy of 70.2% and an AUC of 0.703 were achieved using the MARS model built from the marmoset redox data to classify the human samples as young or old. These results show that common marmosets provide a useful model for thiol redox biology of aging.

Yeast-like chronological senescence in mammalian cells: phenomenon, mechanism and pharmacological suppression

In yeast, chronological senescence (CS) is defined as loss of viability in stationary culture. Although its relevance to the organismal aging remained unclear, yeast CS was one of the most fruitful models in aging research. Here we described a mammalian replica of yeast CS: loss of viability of overgrown "yellow" cancer cell culture. In a density and time (chronological)-dependent manner, cell culture loses the ability to re-grow in fresh medium. Rapamycin dramatically decelerated CS. Loss of viability was caused by acidification of the medium by lactic acid (lactate). Rapamycin decreased production of lactate, making conditioned medium (CM) less deadly. Both deadly CM and lactate caused loss of viability in low cell density, not preventable by either rapamycin or additional glucose. Also, NAC, LY294002, U0126, GSK733, which all indirectly inhibit mTOR and have been shown to suppress the senescent phenotype in traditional models of mammalian cell senescence, also decreased lactate production and decelerated CS. We discuss that although CS does not mimic organismal aging, the same signal transduction pathways that drive CS also drive aging.

Chronological lifespan in stationary culture: from yeast to human cells

A decade ago, Mikhail Blagosklonny predicted that cellular senescence is driven by mitogenic pathways, when the cell cycle is blocked and actual growth is impossible [1]. In particular, the mitogen- and nutrient-sensing mTOR (Target of Rapamycin) pathway drives either cell mass growth or aging [2]. Rapamycin prevents conversion of reversible cell cycle arrest to senescence [3-11]. When the cell cycle is blocked, but mTOR is still active, then cells become senescent. This process was named gerogenic conversion or simply geroconversion [12]. Rapamycin did not by-pass arrest but suppress geroconversion. Cells remained resting but not senescent. The discovery of mTOR-dependent geroconversion allowed Blagosklonny to connect cellular aging to age-related diseases and organismal aging [13, 14]. Furthermore, this predicted that rapamycin is a gerosuppressant, which could be used to prevent age-related diseases by slowing down the aging process [14]. Independently, it was discovered that rapamycin suppresses chronological aging of yeast cells [15]. Chronological lifespan of yeast cells in stationary culture is the most fruitful model in aging research and dozens of papers have been published in Nature, Science, Cell and Cell Cycle. Although yeast model was so useful to identify genes involved in mammalian aging, the reason remained unclear. Yeast only loosely resemble post-mitotic cells in human tissues. Unfortunately, there was no model of mammalian chronological aging in cell culture. In one model developed by Fabrizio and Valter Longo [16] as well as by Matt Kaeberlein and Brian K. Kennedy [17], yeast chronological senescence (CS) is caused by acidosis due to overproduction of acetic acid. Obviously, neither replicative nor accelerated senescence of human cells resembles yeast CS in the stationary culture. Surprisingly, the exact replica was so well known and so trivial that it was overlooked by decades. Here Leontieva and Blagosklonny describe the mammalian cellular model: a neglected flask with overgrown cancer cells that turn medium “yellow” (due to lactate accumulation). Such flasks left and forgotten over weekend could be found in any CO2-incubator. The paper is simultaneously startling and obvious. It is obvious from an everyday experience that highly glycollytic cells can destroy cell culture. But like it was known to most researches (90 years ago) that fungi can destroy bacterial culture, it took a special insight to recognize the potential of this seemingly useless phenomenon. There is an intriguing parallel between penicillin and rapamycin. As described in this issue of Aging, mTOR pathway is involved in glycolytic phenotype, causing self-poisoning due to over-production of lactic acid. By decreasing lactate production, rapamycin prevents chronological senescence (CS). CS can be manipulated genetically and pharmacologically. Most importantly, the same agents that suppress geroconversion, organismal aging and cancer also suppress CS. This study does not break any dogma because there was no dogma as the field did not exist. This paper opens a new filed in both aging and cancer research. Blagosklonny and collaborators are currently preparing follow-up papers with special emphasis to cancer research: the ability of rapamycin to decrease lactate production independently of respiration, selection of highly glycolytic cancer cell clones, tumor progression and resistance to therapy. Many questions will be answered. But this first paper defines the field, providing description of the phenomenon, its mechanism and the ways of pharmacological manipulation. It illuminates the place of yeast CS in aging research and its indirect (via common signaling pathways) relevance to cancer and organismal aging. It also rules out altruistic (programmed) aging of yeast because no one would suspect altruistic nature of cancer cells. I invite the readers to enjoy this first paper in the filed of mammalian cell chronological senescence.

Joint Modeling of Longitudinal Change and Survival

Joint longitudinal-survival models are useful when repeated measures and event time data are available and possibly associated. The application of this joint model in aging research is relatively rare, albeit particularly useful, when there is the potential for nonrandom dropout. In this article we illustrate the method and discuss some issues that may arise when fitting joint models of this type. Using prose recall scores from the Swedish OCTO-Twin Longitudinal Study of Aging, we fitted a joint longitudinal-survival model to investigate the association between risk of mortality and individual differences in rates of change in memory. A model describing change in memory scores as following an accelerating decline trajectory and a Weibull survival model was identified as the best fitting. This model adjusted for random effects representing individual variation in initial memory performance and change in rate of decline as linking terms between the longitudinal and survival models. Memory performance and change in rate of memory decline were significant predictors of proximity to death. Joint longitudinal-survival models permit researchers to gain a better understanding of the association between change functions and risk of particular events, such as disease diagnosis or death. Careful consideration of computational issues may be required because of the complexities of joint modeling methodologies.

In the Laboratory and during Free-Flight: Old Honey Bees Reveal Learning and Extinction Deficits that Mirror Mammalian Functional Decline

Loss of brain function is one of the most negative and feared aspects of aging. Studies of invertebrates have taught us much about the physiology of aging and how this progression may be slowed. Yet, how aging affects complex brain functions, e.g., the ability to acquire new memory when previous experience is no longer valid, is an almost exclusive question of studies in humans and mammalian models. In these systems, age related cognitive disorders are assessed through composite paradigms that test different performance tasks in the same individual. Such studies could demonstrate that afflicted individuals show the loss of several and often-diverse memory faculties, and that performance usually varies more between aged individuals, as compared to conspecifics from younger groups. No comparable composite surveying approaches are established yet for invertebrate models in aging research. Here we test whether an insect can share patterns of decline similar to those that are commonly observed during mammalian brain aging. Using honey bees, we combine restrained learning with free-flight assays. We demonstrate that reduced olfactory learning performance correlates with a reduced ability to extinguish the spatial memory of an abandoned nest location (spatial memory extinction). Adding to this, we show that learning performance is more variable in old honey bees. Taken together, our findings point to generic features of brain aging and provide the prerequisites to model individual aspects of learning dysfunction with insect models.

The effects of aging on dopaminergic neurotransmission: a microPET study of [11C]-raclopride binding in the aged rodent brain

Rodent models are frequently used in aging research to investigate biochemical age effects and aid in the development of therapies for pathological and non-pathological age-related degenerative processes. In order to validate the use of animal models in aging research and pave the way for longitudinal intervention-based animal studies, the consistency of cerebral aging processes across species needs to be evaluated. The dopaminergic system seems particularly susceptible to the aging process, and one of the most consistent findings in human brain aging research is a decline in striatal D2-like receptor (D2R) availability, quantifiable by positron emission tomography (PET) imaging. In this study, we aimed to assess whether similar age effects can be discerned in rat brains, using in vivo molecular imaging with the radioactive compound [ 11C]-raclopride. We observed a robust decline in striatal [ 11C]-raclopride uptake in the aged rats in comparison to the young control group, comprising a 41% decrement in striatal binding potential. In accordance with human studies, these results indicate that substantial reductions in D2R availability can be measured in the aged striatal complex. Our findings suggest that rat and human brains exhibit similar biochemical alterations with age in the striatal dopaminergic system, providing support for the pertinence of rodent models in aging research.

Aged Mice Have Reduced Monocyte Cell-surface Expression Of Antigen-presenting And Co-stimulatory Receptors

Aging is associated with immune dysfunction that is measurable in blood monocytes in humans. Measurements include monocyte concentration, subpopulation proportions and cell-surface receptor expression. Despite widespread use of mouse models in aging research, age-related phenotypical differences in mouse monocytes have not been determined. Purpose. To determine differences in monocyte concentration, supopulation proportions and cell-surface expression of receptors involved in cytokine production, antigen presentation and T-cell activation between young and old mice. Methods. Blood (80 μL) was drawn from the saphenous vein of old (age 80 weeks) and young (age 20 weeks) CD-1 mice. 3-color flow cytometry was used to assess CD115+ monocytes, classic (CD115+/Ly6C+) and non-classic (CD115+/Ly6C-) monocyte subpopulations and their cell-surface expression of toll-like receptor 4 (TLR4), major-histocompatibility complex class II (MHC II), CD80 and CD86. Independent T-tests were used to identify significant (P ≤ 0.05) group differences. Results. Monocyte concentration was 163% greater in old mice (P<0.05) and the proportion of classic monocytes was 70% greater in old mice compared to young (P<0.05). TLR4 expression on classic monocytes was 43% lower in old mice. MHC II expression on non-classic monocytes was 34% lower in old mice (P<0.05). Similarly, CD80 and CD86 expression on non-classic monocytes was significantly lower in old mice compared to young (P<0.05). Conclusion. Increased monocyte concentration and proportion of classic monocytes, the subpopulation preferentially recruited into inflamed tissue, likely indicates immune dysfunction and low-grade inflammation that is routinely detected in aging humans. Lower TLR4 expression in classic monocytes may indicate immune suppression and reduced pro-inflammatory response to infection. Reduced expression of receptors involved in antigen-presentation and T-cell activation on non-classic monocytes, the subpopulation that is maintained in circulation, may further indicate immune suppression in old mice. These findings denote that, like in humans, age-related changes in monocyte cell-surface receptor expression can be detected in mice. Further analysis is necessary to determine the functional consequences of these alterations.

Spontaneous dwarf rat: A novel model for aging research

Dwarf animal models can provide new models for aging research. For the spontaneous dwarf rat (SDR), a dwarf strain derived from the Sprague-Dawley (SD) rat, no data relevant to aging research are available. The present study aimed to examine its growth, hormonal background, lifespan and age-related diseases. Male SDR and SD rats were used for growth comparison and for immunohistochemistry and plasma hormonal analysis. SDR of each sex were maintained until natural death and then inspected pathologically. SDR showed an apparent dwarfism in their youth. Immunohistochemistry indicated that the development of growth hormone (GH)-positive cells in the pituitary was insufficient in SDR. In SDR, plasma GH levels were lower than in SD rats. Moreover, both insulin-like growth factor-1 (IGF-1) and insulin levels were decreased compared to levels in SD rats. Male and female SDR showed a mean lifespan of 29.3 +/- 3.3 and 26.8 +/- 5.3 months, respectively. The main neoplastic lesions in SDR were pituitary and mammary tumors. Major non-neoplastic lesions were incisor malocclusion, heart disease, chronic nephropathy (male) and cerebral hemorrhage (female). Most cases of chronic nephropathy were mild. Compared with longevity data and pathological data reported for SD rats, the lifespan in SDR was increased by 20-40% in males and 10-20% in females, and SDR had characteristic decreases in pituitary and mammary tumors as well as in severe chronic nephropathy. The SDR, differing in endocrinology, longevity and pathology from the SD rat, is potentially a new animal model for aging research.

Rodent models of brain aging and neurodegeneration

Laboratory rats and mice have long been considered to be convenient models for the study of aging in various mammalian systems. With regard to functions of the central nervous system, rodents have anatomical, cellular, and molecular characteristics that are similar to humans, and they can be tested for behavioral analogues of basic human motivational, reflexive and psychomotor functions, as well as for higher-order brain functions such as learning, memory and cognition. Behavioral studies of rodents conducted in the 1970’s and 1980’s provided confirmation that rodents indeed exhibit age-related declines in cognitive and psychomotor functions across their relatively short life spans. While it was clear that these declines did not reflect neurodegenerative conditions like Alzheimer’s or Parkinson’s diseases, it nevertheless became feasible to study the biological basis of the age related impairments in higher-order brain functions of these species. Moreover, rodent models of brain aging were recognized as potentially useful for predicting the effectiveness of therapeutic interventions on functional aging in humans. Research focused on age-related neurodegenerative diseases moved in a different direction, employing anatomical, pharmacological, and genetic manipulations to mimic neurodegenerative conditions. However, the behavioral characterization of the rodent models at different ages has been an essential element in both types of research, and has provided the most critical evidence needed to evaluate hypotheses about the neurobiological basis of brain aging and neurodegenerative disease. Efforts employing rodent models to identify the causes of brain aging and neurodegenerative conditions gained significant momentum in the 1990s, and many research programs and their methods of investigation have matured during the first half of the current decade. Three of the papers in the current issue discuss methodological approaches based on an earlier observation that age-related declines of cognitive function in rodents differ in severity among individuals, as appears to be the case in human subjects. Such trends are often reflected in an age-related increase of variability between test subjects, or as the presence of an apparent subset of aged animals that show reliable cognitive impairment. The application of methods to identify the specific neurobiological substrates that correlate with individualized cognitive performance of old rodents has led to significant advances in understanding of the effects and potential causes of brain aging. In particular, one article in this issue illustrates some novel insights gleaned through implementation of this type of methodology in conjunction with microarray profiling. A traditional approach to understanding processes of biological aging has been to study models or conditions in which the timetables of various age-related endpoints appear to be decelerated or accelerated. Such approaches have been equally attractive in brain aging and neurodegeneration research, as illustrated in two review articles in the current issue. These reviews provide new insights with regard to the potential influence of cerebral ischemia and disrupted circadian rhythms on cognitive function during aging. Long-standing practical and theoretical issues regarding the use of rodent models in aging research are widely considered in this issue. The availability of aged mice and rats as a critical resource has permitted a remarkable growth in brain aging research programs, but has simultaneously (and quite unavoidably) influenced the nature of the investigations by virtue of the specific genotypes that have been available. Articles in the current issue illustrate the use of a variety of different mouse and rat genotypes and discuss the extent to which they are appropriate models when used in different types of brain aging or neurodegeneration research. Additionally, one article illustrates assessment of decline in cognitive and psychomotor function in aging non-human primates, and addresses theoretical issues having a significant impact on the validity of various rodent models of brain aging. The common element among the articles appearing in this issue is a focus on behavioral assessment of aging in higher-order functions of the brain, the organ that must be considered closely linked to many important components of successful aging. While the life span has been considered a “gold standard” for evaluating potential anti-aging interventions in rodents, assessment of life span alone may fail to fully address the critical question of whether or not the productive, independent periods of life can be extended. While diverse in their individual focus, the articles in this issue are all reflective of progress toward an improved “standard” for understanding and predicting successful aging.

Glutathione‐S‐transferase expression in the brain: possible role in ethanol preference and longevity

Identification of genes that are differentially expressed in rats bidirectionally selected for alcohol preference might reveal biological mechanisms underlying alcoholism or related phenotypes. Microarray analysis from medial prefrontal cortex (mPFC), a key brain region for drug reward, indicated increased expression of glutathione-S-transferases of the alpha (Gsta4) and mu (Gstm1-5) classes in ethanol-preferring AA rats compared with nonpreferring ANA rats. Real-time RT polymerase chain reaction (RT-PCR) analysis demonstrated approximately 2-fold higher Gsta4 transcript levels in several brain regions of ethanol-naive AA compared with ANA rats. Differences in mRNA levels were accompanied by differential levels of GSTA4 protein. We identified a novel haplotype variant in the rat Gsta4 gene, defined here as var3. Allele frequencies of var3 were markedly different between AA and ANA rats, 52% and 100%, respectively. Gsta4 expression was strongly correlated with the gene dose of var3, with approximately 60% of the variance in expression accounted for by genotype at this locus. The contribution of glutathione S-transferase expression to the ethanol-preferring phenotype is presently unclear. It could, however, underlie observed differences in life span between AA and ANA lines, prompting a utility of this animal model in aging research.

Of Mice and Monkeys: National Institute on Aging Resources Supporting the Use of Animal Models in Biogerontology Research

The preponderance of our understanding of the biological changes that occur with aging has come from studies using rodents. Rodents are a valuable model for biogerontology research because of similarities to humans in the physiology and cell biology of aging. There are, however, many differences between rodents and humans, so application of findings in rodents to human aging requires the use of a model that is closer to humans at the genetic and physiological level. In aging research, the macaque has filled this need. There are many challenges associated with using nonhuman primates in aging research, not the least of which are the limited availability of aged monkeys and the cost of using them. To facilitate this research, the National Institute on Aging has developed several resources to assist investigators and promote the use of the nonhuman primate model in aging research.

Long‐lived yeast as a model for ageing research

Yeast has essentially two lifespans: a replicative lifespan (the number of daughters produced by each dividing mother cell) and a chronological lifespan (the capacity of stationary (G0) cultures to maintain viability over time). There is a tendency now to label every investigation that addresses these lifespans as ageing research. It is, though, analyses of the longest lifespans that will be most informative about the determinants of longevity and yield results most relevant to ageing in more complex systems. This review addresses these issues and describes the ongoing studies that are now attempting to address ageing in yeast cells of maximal replicative or chronological longevity.

High-resolution respirometry–a modern tool in aging research

Alterations in mitochondrial function are believed to play a major role in aging processes in many species, including fungi and animals, and increased oxidative stress is considered a major consequence of altered mitochondrial function. In support of this theory, a lot of correlative evidence has been collected, suggesting that changes in mitochondrial DNA accumulate with age in certain tissues. Furthermore, genetic experiments from lower eukaryotic model organisms, indicate a strong correlative link between increased resistance to oxidative stress and an extended lifespan; in addition, limited experimental evidence suggests that the inhibition of mitochondrial function by selected pharmacologically active compounds can extend lifespan in certain species. However, changes in mitochondrial function may affect aging in a different way in various tissues, and a clear statement about the role of mitochondrial deterioration during physiological aging is missing for most if not all species. At this point, respirometric analyses of mitochondrial function provide a tool to study age-associated changes in mitochondrial respiratory chain function and mitochondrial ATP production within living cells and isolated mitochondria. In the recent years, new instruments have been developed, which allow for an unprecedented high-resolution respirometry, which enables us to determine many parameters of mitochondrial function in routine assays using small samples of biological material. It is conceivable that this technology will become an important tool for all those, who are interested in experimentally addressing the mitochondrial theory of aging. In this article, we provide a synopsis of traditional respirometry and the advances of modern high-resolution respirometry, and discuss how future applications of this technology to recently established experimental models in aging research may provide exciting new insights into the role of mitochondria in the aging process.

Comparative aspects of zebrafish ( Danio rerio) as a model for aging research

The zebrafish has emerged over the past decade as a major model system for the study of development due to its invertebrate-like advantages coupled with its vertebrate biology. These features also make it a potentially valuable organism for gerontological research. The main advantages of zebrafish include its economical husbandry, small yet accessible size, high reproductive capacity, genetic tractability, and a large and growing biological database. Although zebrafish life span is longer than rodents, it shares the feasibility of large-scale mutational analysis with the extremely short-lived invertebrate models. This review compares zebrafish with the more widely used model organisms used for aging research, including yeast, worms, flies, mice, and humans.

Mnsod overexpression extends the yeast chronological (G(0)) life span but acts independently of Sir2p histone deacetylase to shorten the replicative life span of dividing cells.

Studies in Drosophila and Caenorhabditis elegans have shown increased longevity with the increased free radical scavenging that accompanies overexpression of oxidant-scavenging enzymes. This study used yeast, another model for aging research, to probe the effects of overexpressing the major activity protecting against superoxide generated by the mitochondrial respiratory chain. Manganese superoxide dismutase (MnSOD) overexpression increased chronological life span (optimized survival of stationary (G(0)) yeast over time), showing this is a survival ultimately limited by oxidative stress. In contrast, the same overexpression dramatically reduced the replicative life span of dividing cells (the number of daughter buds produced by each newly born mother cell). This reduction in the generational life span by MnSOD overexpression was greater than that generated by loss of the major redox-responsive regulator of the yeast replicative life span, NAD+-dependent Sir2p histone deacetylase. It was also independent of the latter activity. Expression of a mitochondrially targeted green fluorescent protein in the MnSOD overexpressor revealed that the old mother cells of this overexpressor, which had divided for a few generations, were defective in segregation of the mitochondrion from the mother to daughter. Mitochondrial defects are, therefore, the probable reason that MnSOD overexpression shortens replicative life span.

Apoptosis in yeast: a new model for aging research

Apoptosis is a form of programmed cell death with a central role in development and homeostasis of metazoan organisms. Recent research indicates the presence of an apoptotic cell death program in unicellular eukaryotes. Yeast can be killed by expression of mammalian proapoptotic genes or in response to oxygen stress, which is an inducer of mammalian apoptosis. The dying yeast cells show morphological alterations typical for apoptosis. Yeast provides a simple model for cellular aging. The observation that old yeast cells produce oxygen radicals and die apoptotically may provide clues to a similar sequence of events in mammalian aging.

The budding yeast, Saccharomyces cerevisiae, as a model for aging research: a critical review

In this review we discuss the yeast as a paradigm for the study of aging. The budding yeast Saccharomyces cerevisiae, which can proliferate in both haploid and diploid states, has been used extensively in aging research. The budding yeast divides asymmetrically to form a ‘mother’ cell and a bud. Two major approaches, ‘budding life span’ and ‘stationary phase’ have been used to determine ‘senescence’ and ‘life span’ in yeast. Discrepancies observed in metabolic behavior and longevity between cells studied by these two systems raise questions of how ‘life span’ in yeast is defined and measured. Added to this variability in experimental approach and results is the variety of yeast strains with different genetic make up used as ‘wild type’ and experimental organisms. Another problematic genetic point in the published studies on yeast is the use of both diploid and haploid strains. We discuss the inherent, advantageous attributes that make the yeast an attractive choice for modern biological research as well as certain pitfalls in the choice of this model for the study of aging. The significance of the purported roles of the Sir2 gene, histone deacetylases, gene silencing, rDNA circles and stress genes in determination of yeast ‘life span’ and aging is evaluated. The relationship between cultivation conditions and longevity are assessed. Discrepancies between the yeast and mammalian systems with regard to aging are pointed out. We discuss unresolved problems concerning the suitability of the budding yeast for the study of basic aging phenomena.